IVIG and rituximab for treatment of chronic antibody-mediated rejection: a prospective study in paediatric renal transplantation with a 2-year follow-up

Abstract

Summary Chronic antibody‐mediated rejection (AMR) is the major cause of late renal allograft loss. There is, however, no established treatment for this condition. We report the results of a prospective pilot study on an antihumoral therapy (AHT) consisting of high‐dose intravenous immunoglobulin G (IVIG) and rituximab in 20 paediatric renal transplant recipients. Donor‐specific HLA antibodies (HLA DSA) were quantified by Luminex‐based bead array technology. Loss of eGFR decreased significantly from 7.6 ml/min/1.73 m² during 6 months prior to AHT to 2.1 ml/min/1.73 m² (P = 0.0013) during 6 months after AHT. Fourteen patients (70%) responded: nine of nine patients (100%) without and five of 11 (45%) with transplant glomerulopathy (P = 0.014). C4d positivity in PTC decreased from 40 ± 18.5% in the index biopsy to 11.6 ± 12.2% (P = 0.002) in the follow‐up biopsy. In four of nine biopsies (44%) C4d staining turned negative. During 2 years of follow‐up, the median loss of eGFR in each of the four 6‐month periods remained significantly lower compared with prior to AHT. Class I DSA declined in response to AHT by 61% (p = 0.044), class II DSA by 63% (p = 0.033) 12 months after intervention. AHT with IVIG and rituximab significantly reduces or stabilizes the progressive loss of transplant function in paediatric patients with chronic AMR over an observation period of 2 years, apparently by lowering circulating DSA and reducing intrarenal complement activation.

Acute and chronic antibody-mediated rejection in pediatric kidney transplantation

“…Fig. 3 Algorithm for diagnosis and treatment of chronic antibody-mediated rejection according to Billing et al [63] CAMR is the main cause of long-term graft loss. The diagnosis with transplant glomerulopathy and/or transplant vasculopathy as criteria is straightforward.…”

“…In a larger trial with 20 patients and a 2-year follow-up, the researchers confirmed that the decrease of GFR could be significantly reduced over 2 years by this combination treatment, and the response rate was 70 %. This result was associated with a 61 % decrease in HLA class I antibodies and a 63 % decrease in HLA class II antibodies [63]. A study in adults showed that a combination of this regimen with plasmapheresis therapy can further improve these results [64].…”

Management of proteinuria in the transplanted patient

“…In a pediatric study by Billing et al [34], all 20 children with CAMR had proteinuria and 35 % of them had nephrotic-range proteinuria. Based on the results of these studies, transplant glomerulopathy would appear to be a negative prognostic factor for both proteinuria and graft loss.…”

Comparison of the Treatment Efficacy of Rituximab and Plasmapheresis/Intravenous Immunoglobulin Combination with Historical Control in Chronic Antibody Mediated Rejection

“…Anti-HLA Class II antibodies reported to be strongly related to development of TG in a large cohort of kidney transplant recipients (8). Regarding the chronic AMR, the presence of transplant glomerulopathy has been shown to be inversely correlated with allograft survival and treatment response (8)(9)(10).…”

“…Thus, there are no well-established guidelines or approved treatment for chronic AMR, recently a numerous of studies have been published about the influence of rituximab (a monoclonal anti-CD 20 antibody) alone or combination with intravenous immunoglobulin G (IVIG) on progression and outcomes of chronic AMR with inconsistent results (4,(9)(10)(11)(12)(13). These studies were mostly retrospective, and have distinct inclusion criteria and end points for evaluation of response.…”